Clinical signs and symptoms in a large hereditary spastic paraparesis pedigree with a novel spastin mutation

Abstract

The most common form of autosomal dominant hereditary spastic paraparesis (HSP), SPG4, is caused by mutations in the spastin gene on chromosome 2p. This disease is characterized by intra- and interfamilial phenotypic variation. To determine the predictive values of clinical signs and symptoms in SPG4, we examined 43 members of a large pedigree with autosomal dominant HSP. We then identified the genetic etiology of the disorder in this family, a novel nonsense mutation in exon 1 of spastin, carried by 24 of the examined family members. The best clinical predictors of positive gene status were the presence of hyperreflexia in the lower extremities, >2 beats of ankle clonus, pes cavus, bladder symptoms and increased tone in the legs. The mean age of onset was 32.2 +/- 7.4 years, but the age of onset was earlier in children from 10 of 12 child-parent gene-positive pairs, with a mean difference of 10.8 +/- 3.3 years. The finding of leg weakness was especially common in older-onset affected family member with leg hyperreflexia. These results suggest that specific clinical signs and symptoms may be of value in differentiating individuals affected with SPG4 from family members with nonspecific neurological findings.

Large deletion mutation of SPAST in a multi‐generation family from Sardinia

“…The clinical features observed in the 'Nulvi kindred' (NK) À the largest pedigree thus far described with a single genomic deletion encompassing SPAST and the flanking SLC30A6 À did not seem to differ greatly from those observed in other kindred harboring large SPAST deletions, although the mean onset age is higher than was previously reported [5][6][7]. At our latest examination 25% of patients (median age 37.5 AE 14.8 years) were asymptomatic, and 16% had minimal neurological signs.…”

The Neuropsychiatry of Hyperkinetic Movement Disorders: Insights from Neuroimaging into the Neural Circuit Bases of Dysfunction

“…70 Only a small number of HDL2 cases with comorbid neuropsychiatric illness have been reported in the literature, but they are notable for the heterogeneity of associated symptoms, including depression, anxiety, and psychosis, in addition to a frontal-dysexecutive syndrome leading to dementia. [72][73][74][75] While neuropsychiatric comorbidity appears to be the rule rather than the exception in HDL2, it may differ from the other neuroacanthocytoses in that neuropsychiatric symptoms seem to be reported only after the onset of neurological illness.…”

The Neuropsychiatry of Hyperkinetic Movement Disorders: Insights from Neuroimaging into the Neural Circuit Bases of Dysfunction

“…Only a small number of HDL2 cases with comorbid neuropsychiatric illness have been reported in the literature, but they are notable for the heterogeneity of associated symptoms, including depression, anxiety, and psychosis, in addition to a frontal-dysexecutive syndrome leading to dementia 72–75. While neuropsychiatric comorbidity appears to be the rule rather than the exception in HDL2, it may differ from the other neuroacanthocytoses in that neuropsychiatric symptoms seem to be reported only after the onset of neurological illness.…”